A recent Signal Transduction and Targeted Therapy study summarized the structure of inflammasomes and their role in diseases. This study also explored the therapeutic potential of inflammasomes against several conditions.
Study: The role of inflammasomes in human diseases and their potential as therapeutic targets. Image Credit: Gorodenkoff/Shutterstock.com
What are inflammasomes?
The innate immune responses protect humans from environmental irritants, pathogens, and tissue damage.
This protection mechanism is partially associated with the triggering of inflammation after recognizing a foreign pathogenic component in the body. The inflammatory response is caused by large protein complexes known as inflammasomes.
In 1985, Hanazawa and colleagues revealed that exposure to lipopolysaccharide (LPS) triggers the production of interleukin-1 (IL-1) in murine peritoneal macrophages.
However, the term inflammasome was coined only in 2002. The first inflammasome, namely, NACHT, LRR, and PYD domains-containing protein 1 (NLRP1), was identified in the same year.
The general structure of inflammasomes
Scientists have uncovered the structures of NLRP1, NLRP3, NLRC4, and AIM2 molecules. In the case of the Human NLRP1 gene, multiple alternatively spliced transcript variants that encode up to five distinct isoforms have been found.
The longest isoform is encoded by NLRP1 transcript variant 1, which is known as isoform 1.
This isoform contains many conservative domains including PYD (Pyrin death domain), NOD2_WH (NOD2 winged helix) domain, NACHT domain, LRR_RI (LRRs, ribonuclease inhibitor RI-like subfamily) domain, FIIND (function to find) domain, and NLRC4_HD2 (NLRC4 helical domain).
In comparison to isoform 1, isoform 2 is devoid of an internal segment of the FIIND domain; whereas isoform 3 lacks an internal segment in the LRR_RI domain. In the case of isoform 4, two internal segments are absent in the FIIND and LRR_RI domains.
Isoform 5 exhibited a shorter and distinct C-terminus. The functional difference in these isoforms must be elucidated in future studies. The single nucleotide polymorphism in the genome has been associated with specific diseases.
For instance, rs11651270 (M1184V) has been linked with the manifestations of asthma.
Similarly, Human NLRP3, NLRC4 gene, and AIM2 genes contain many alternatively spliced transcript variants. It must be noted that NLRP9 inflammasomes greatly differ from other inflammasomes.
Important role of inflammasomes in diseases
Several studies have established a robust association between inflammasomes and various autoimmune and autoinflammatory diseases, such as metabolic disorders, cardiovascular diseases, and neurodegenerative diseases.
Several cardiovascular diseases are developed due to inflammation and aberrant inflammasome activity. In the case of atherosclerosis, inflammasome activation causes an elevated production of IL-18 that contributes to the disease pathology.
Increased levels of low-density lipoprotein (LDL) and free fatty acids (FFAs) in the blood trigger the production of pro-IL-1β. CD36 triggers cholesterol crystallization and oxidized LDL internalization, which activates NLRP3 inflammasome via phagolysosomal impairment. This study implies that LDL and FFAs act as inflammasome activation signals.
Many in vivo animal experiments have indicated hypertension-induced cardiac upregulation of NLRP3. These experiments observed that transverse aortic constriction (TAC) enhances NLRP3 and caspase-1 activity in cardiomyocytes.
Therefore, the original activation site of NLRP3 could be cardiomyocytes. Besides hypertension, inflammasomes also regulate the propagation of venous thromboembolism (VTE).
NLRP3 is expressed in microglia, neurons, astrocytes, and oligodendrocytes. This inflammasome has been associated with several cerebral pathologies including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and central nervous system (CNS) infections.
Recently, inflammasome activation was correlated with an increased risk of cognitive deficits in AD patients.
Studies have shown that the functional NLRP3 proteins are associated with neuroinflammation of neurodegenerative diseases. However, the exact mechanism of action is still unclear. It is important to understand whether different inflammasomes act synergistically or independently for disease activation.
Pathogenesis of several respiratory disorders including chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and pulmonary infection, are associated with inflammasomes.
For instance, upregulated expression of NLRP3 and IL‐1β genes was found in asthmatic patients. Besides the aforementioned diseases, different inflammasomes have been found to be associated with the manifestation of digestive, urogenital, and blood and lymphatic system disorders.
Development of inflammasome-targeted therapy
Many inflammasomes that are linked with various diseases have been identified. Therefore, inflammasome signaling pathways could be used as potential therapeutic targets for developing novel treatments.
At present, several drugs that target inflammasome-related pathways have received approval for commercial use. However, none of the drugs directly target inflammasomes.
Recently, scientists have focused on developing inhibitors of inflammasome sensor proteins for therapeutic purposes. Tranilast, a drug used to treat allergies, was found to prevent NLRP3 assembly via direct binding to the NACHT domain.
Other available drugs or compounds that inhibit inflammasomes are CY-09, N-benzyl 5-(4-sulfamoylbenzylidene-2-thioxothiazolidin-4-one analogs), oridonin, and tetrahydroquinoline.
A recent study reported that several bioactive compounds extracted from medicinal plants can inhibit NLRP3 or AIM2 inflammasome.
For instance, costunolide is a bioactive compound extracted from Saussurea lappa, a medicinal herb, which can bind to Cys598 in the NACHT domain of NLRP3.
Both laboratory and clinical trials have observed promising results while assessing inflammasome-targeted strategies. Considering the role of inflammasomes in multiple diseases, it must be explored to develop more novel treatment strategies in the future.
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